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c-Maf controls immune responses by regulating disease-specific gene networks and repressing IL-2 in CD4+ T cells

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journal contribution
posted on 17.07.2020 by Leona Gabryšová, Marisol Alvarez Martinez, Raphaëlle Luisier, Luke S Cox, Jan Sodenkamp, Caroline Hosking, Damián Pérez Mazliah, Charlotte Whicher, Yashaswini Kannan, Krzysztof Potempa, Xuemei Wu, Leena Bhaw, Hagen Wende, Michael H Sieweke, Greg Elgar, Mark Wilson, James Briscoe, Vicki Metzis, Jean Langhorne, Nicholas M Luscombe, Anne O'Garra
The transcription factor c-Maf induces the anti-inflammatory cytokine IL-10 in CD4+ T cells in vitro. However, the global effects of c-Maf on diverse immune responses in vivo are unknown. Here we found that c-Maf regulated IL-10 production in CD4+ T cells in disease models involving the TH1 subset of helper T cells (malaria), TH2 cells (allergy) and TH17 cells (autoimmunity) in vivo. Although mice with c-Maf deficiency targeted to T cells showed greater pathology in TH1 and TH2 responses, TH17 cell–mediated pathology was reduced in this context, with an accompanying decrease in TH17 cells and increase in Foxp3+ regulatory T cells. Bivariate genomic footprinting elucidated the c-Maf transcription-factor network, including enhanced activity of NFAT; this led to the identification and validation of c-Maf as a negative regulator of IL-2. The decreased expression of the gene encoding the transcription factor RORγt (Rorc) that resulted from c-Maf deficiency was dependent on IL-2, which explained the in vivo observations. Thus, c-Maf is a positive and negative regulator of the expression of cytokine-encoding genes, with context-specific effects that allow each immune response to occur in a controlled yet effective manner.